Frank F. Davis, pegylation pioneer, dies at 100

Frank F. Davis, who first came up with the idea of pegylation—attaching polyethylene glycol (PEG) to a protein to help it escape the body’s immune response—died May 19. He was 100.

Davis was born in 1920 in Pendleton, Oregon. He got his first job in the early 1940s repairing airplanes—work that took him to Eritrea, Iran, and Northern Ireland during World War II, until he was drafted into the US Navy.

After the war, Davis earned his bachelor’s degree in chemistry at the University of Hawaii in 1950 and his PhD from the University of California, Berkeley in 1955. After completing his postdoctoral studies, he joined the Rutgers University faculty in 1958. It was there that Davis invented pegylation.

“In the late 1960s when I was, as they say, between grants, I became interested in developing a procedure whereby selected bioactive proteins could be utilized for human therapy,” Davis wrote in a commentary about the discovery (Adv. Drug Deliv. Rev. 2002, DOI: 10.1016/s0169-409x(02)00021-2).

Most non-human proteins cause adverse immune reactions when injected into people, limiting their therapeutic value. Davis thought a polymer might give non-human proteins a protective cloak. He read in a medical journal that doctors had safely injected a copolymer that included PEG into patients undergoing major blood-vessel surgery to prevent lipid embolisms. So he decided to covalently link PEG to the enzyme bovine liver catalase.

When injected into mice, the pegylated enzyme didn’t elicit the same immunogenic response as the naked enzyme did, and it also lasted longer before being broken down biologically. Davis patented the discovery (US Patent No. 4,179,337) and, in 1986, cofounded Enzon Pharmaceuticals with Abraham Abuchowski to commercialize it.

Enzon’s first drug, Adagen, a pegylated version of the enzyme adenosine deaminase, was approved by the US Food and Drug Administration in 1990 to treat severe combined immunodeficiency disease, also known as bubble boy disease. The FDA has since approved more than 15 pegylated drugs including Mircera, for anemia in patients with chronic kidney disease, and Neulasta, which boosts white blood cell counts after cancer chemotherapy. Many pegylated drug candidates are in clinical trials, and pegylated lipids help stabilize the nanoparticles that encase the mRNA in COVID-19 vaccines from Pfizer-BioNTech and Moderna.

“Frank Davis made major contributions to drug delivery and really changed the field,” says Massachusetts Institute of Technology drug delivery expert Robert S. Langer in an email. Langer notes that many companies, including Enzon, “created new life saving pharmaceuticals because of the work Frank did.”